Friday, October 12, 2012

It’s not the crime, it’s the cover-up: reactivity in the developing brain and the emergence of schizophrenia

In thinking about the causes of
schizophrenia, a central question keeps coming up: why does the brain end up in
that particular state? Despite a high degree of variability in presentation and
difficulties in defining it precisely, there is a recognisable syndrome that we
call schizophrenia. This has a number of characteristic attributes, most
striking of which are psychotic symptoms such as hallucinations, delusions and
disorganised thoughts. These are truly, deeply strange phenomena that require
an explanation: why do brain systems fail in that particular way? More to the
point, why does that particular brain state emerge in so many people from so many
different initial causes?

Because though we don’t know all the causes
of this disorder, we know for sure that there are a lot of them. On the genetic front, a large number of distinct, rare mutations in different genes (or
regions of the genome) are associated with a high risk for schizophrenia. Genome-wide
association studies have implicated additional loci that may modify risk
weakly. There are also many environmental risk factors identified through
epidemiological studies, such as maternal infection, cannabis use, migration,
urban living, winter birth, obstetric complications and others, each of which
modestly increases risk, statistically-speaking. Currently, we do not know how
all these risk factors interact and there is ongoing debate about their
relative importance. What we can say with certainty, however, is that the
causes of this disorder are extremely heterogeneous.

The other thing that there is general
agreement on is that schizophrenia is a neurodevelopmental disorder. Even
though the overt symptoms of psychosis or cognitive decline do not emerge until
adolescence or even later, the evidence is compelling that in most cases the
initial insults probably occurred decades earlier during fetal or postnatal
development. So, the question becomes: why do defects in neural development of
so many different types all lead to this same, strange condition? Why is
psychosis such an easy phenotype to get to?

This is where Richard Nixon comes in.

The Watergate scandal inspired the saying
“it’s not the crime, it’s the cover-up that gets you”*. In regard to
schizophrenia, the idea is that mutations in various genes (or environmental
insults) may disrupt neural development in diverse ways, affecting different
cellular processes and causing different primary phenotypes. The reason that
all these different insults can lead to the same outcome lies in the way the developing
brain reacts (or over-reacts) to them.

This idea is appealing because it is very
parsimonious – it provides a common pathway to the end-state we recognise as
schizophrenia, even from extremely diverse starting points. It can also explain
the high incidence of the condition: mutations in many, many different genes
can cause the disorder because it is an emergent property of the developing brain
and not related directly to the genes’ primary functions. It also has a lot of
experimental support, especially for the example of psychosis, where many
investigations have highlighted a central role for the dopamine system.

Dopamine attracted attention because both
typical and atypical antipsychotics target the dopamine D2 receptor and their
efficacy is related to their affinity for this receptor. Conversely, amphetamine,
which increases dopamine levels, can induce psychotic symptoms. More direct evidence
of changes in the dopamine system comes from imaging studies of schizophrenia
patients, which have found alterations in dopamine synthesis and release and in
baseline occupancy of D2 receptors in the striatum. These findings are
complicated and not uncontroversial, but the general convergence of different
lines of evidence strongly supports the model that a disturbance in
dopaminergic signaling is causing psychosis (or at least contributing to it).

This led many people to look for variation
in genes encoding components of the dopaminergic system in patients with
schizophrenia, without success. No variation in these genes was found to be
associated with risk of the disease. This does not undermine the association of
dopamine with the state of psychosis – it simply suggests that the primary
changes are in other systems and that the alterations to the dopamine system
are secondary reactions.

Animal models have shown how such changes
can come about. Many different animal models have been generated to try and
model aspects of schizophrenia. Some expose animals to known environmental risk
factors, others use pharmacological or surgical procedures and, more recently,
a growing number recapitulate high-risk mutations in mice.

With a couple exceptions, none of these
manipulations targets the dopamine system directly. Nevertheless, in many of
these models, an altered state of dopamine signaling emerges. This can be
observed in a suite of behaviours (such as hyperlocomotion and altered
pre-pulse inhibition), which are characteristic of animals in which the
dopamine system is hyper-responsive. Many of these animal models show reversal
of these phenotypes with antipsychotics and heightened sensitivity to drugs
like amphetamine. Alterations in dopamine release, in levels of dopamine
receptors or other parameters have also been directly observed in some models.

So, the evidence from animal models
converges with that from humans – changes to the dopaminergic system can emerge
as secondary consequences of a range of different primary insults. One model
has been particularly informative as to how these changes can come about. If
young postnatal rats are given a lesion to a particular brain region, the
ventral hippocampus, then they will later – only after rat “adolescence” –
develop symptoms that parallel psychosis in humans, as described above. These
symptoms can be reversed by antipsychotics and are correlated with changes in
dopaminergic signaling, but these arise in very different regions of the brain
to the one with the lesion.

The circuitry driving these changes has
been worked out in great detail by Anthony Grace, Patricio O’Donnell and their
respective colleagues. The lesion to the ventral hippocampus renders the
connected region, the ventral subiculum hyperactive. In turn, this region
projects to part of the midbrain, where most dopaminergic neurons live. It leads to
excessive dopamine neuron excitability, which alters the drive to the target
areas of these neurons in the striatum and cortex. Crucially, the development of
these areas in turn, is changed as they develop under a regime of altered
activity.

The initial connectivity of the brain is
specified by a molecular program of axon guidance and synaptic connectivity
cues, but this generates only a rough map. This scaffold is extensively
modified by activity. The developing brain is not silent – it is extremely
active, electrically. It has its own rhythms and modes of activity, quite
different from adults, and these intrinsically generated patterns of electrical
firing are essential for driving the wiring of neuronal circuits. Any defect in
initial wiring that results in altered architecture of local circuits is likely
to also alter patterns of activity, which will propagate through developing
circuits to connected areas, inducing a cascade of knock-on effects.

In some cases, neurons may attempt tocompensate for altered levels of activity, but these attempts actually
exacerbate the situation, compounding the initial defect. This can happen in
particular in cases where the initial molecular defect impairs not just the
patterns of activity but the systems that monitor and interpret that activity.
Neurons may be getting excessive activity but “think” they are getting less,
causing what would normally be homeostatic responses to instead amplify the
initial difference.

So, changes in dopaminergic signaling in
cortex and striatum – the signatures of psychosis – can emerge as very
downstream effects of diverse initial disturbances in brain development. This
is by no means the whole explanation of the state we call schizophrenia or even
of the symptoms of psychosis, but it certainly seems to contribute to it. There
are many other changes that also emerge over development in both human patients
and animal models, notably including a suite of biochemical changes in particular
inhibitory interneurons in the cortex. Again, the pathways through which these
changes come about are beginning to be worked out.

In this model, the phenotype of
schizophrenia is an emergent property of the developing brain – it is not
linked in any direct way to the primary etiological factors. In the plot of a
classic farce, a minor misunderstanding leads to catastrophe when the hapless
protagonist overcompensates for it, getting himself into deeper and deeper
trouble (think Basil Fawlty). Things get progressively out of hand and hilarity
ensues. When the equivalent happens in brain development, insanity ensues.

*With thanks to David Dobbs for the meme,
which came up in a really interesting conversation on how genotypes relate to
psychological phenotypes (very indirectly).

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